I. Description And Characterization Of Glaucoma
Glaucoma is an ophthalmologic disorder responsible for visual impairment. It is the fourth most common cause of blindness and the second most common cause of visual loss in the United States, and the most common cause of irreversible visual loss among African-Americans. Generally speaking, the disease is characterized by a progressive neuropathy caused at least in part by deleterious effects resulting from increased intraocular pressure on the optic nerve. In normal individuals, intraocular pressures range from 12 to 20 mm Hg., averaging approximately 16 mm Hg. However, in individuals suffering from glaucoma, intraocular pressures generally rise above 25 to 30 mm Hg. and can sometimes reach 70 mm Hg. Importantly, the loss of vision can result from intraocular pressures only slightly above or even within the statistically normal range, in eyes which are unusually pressure-sensitive, over a period of years. Moreover, extremely high pressures (e.g., 70 mm Hg.) may cause blindness within only a few days. [See, e.g., P. L. Kaufman and T. W. Mittag, "Medical Therapy Of Glaucoma," Ch. 9, Sec. II (pp. 9.7-9.30) In P. L. Kaufman and T. W. Mittag (eds.): Glaucoma (Vol. 7 of S. M. Podos and M. Yanoff (eds): Textbook of Ophthalmology Series). London, Mosby-Year Book Europe Ltd. (1994); A. C. Guyton, Textbook of Medical Physiology (W. B. Saunders Co., Sixth Ed.), pp. 386-89 (1981)].
Several different types of glaucomas exist, each having different pathophysiologies and risk factors. In terms of classification, glaucomas may first be deemed to be either "primary" or "secondary." Primary glaucomas, discussed further below, result directly from anatomical and/or physiological disturbances in the flow of aqueous humor (i.e., intraocular fluid). Secondary glaucomas occur as a sequel to ocular injury (e.g., trauma inflicted to the eye) or preexisting disease (e.g., an intraocular tumor or an enlarged cataract). Though the various secondary glaucomas have different etiologies, they are similar to the primary glaucomas in that they all produce visual loss through optic neuropathy.
The major types of primary glaucomas include (i) open-angle glaucoma (also known as chronic or simple glaucoma), (ii) angle-closure glaucoma (also known as closed-angle or narrow-angle glaucoma), and (iii) congenital glaucoma (also known as infantile glaucoma).
Open-Angle glaucoma constitutes approximately 90% of all primary glaucomas. Open angle glaucoma is characterized by abnormally high resistance to fluid drainage from the eye. Intraocular pressure rises to the level required to drive the fluid normally produced by the eye, whose rate of formation is not altered in glaucoma, across the elevated resistance, according to the normal laws of physics governing passive bulk fluid flow across a resistance and down a pressure gradient. Normal resistance is required to maintain an intraocular pressure sufficient to: (i) maintain the shape of the eye (i.e., to keep it inflated) for optical integrity, and (ii) provide a pressure gradient to allow for the flow of aqueous humor, a fluid produced by the eye which provides for the metabolic needs of the avascular cornea and lens. This resistance is provided by the trabecular meshwork, a complex tissue consisting of specialized endothelial cells, connective tissue bearns, and extracellular matrix.
Angle-closure glaucoma entails closure or blockage of the anterior chamber angle by another ocular structure (usually the iris), thereby restricting outflow of aqueous humor. Though angle-closure glaucoma only constitutes approximately 5% of primary glaucomas, it requires immediate medical attention. [See, e.g., P. L. Kaufman and T. W. Mittag, "Medical Therapy Of Glaucoma," Ch. 9, Sec. II (pp. 9.7-9.30) In P. L. Kaufman and T. W. Mittag (eds.): Glaucoma (Vol. 7 of S. M. Podos and M. Yanoff (eds): Textbook of Ophthalmology Series). London, Mosby-Year Book Europe Ltd. (1994)].
II. Etiology Of Glaucoma
Glaucoma has been associated with both pharmacological and non-pharmacological factors. Non-pharmacological factors include age, race, family history, diabetes, and blood pressure. For example, African Americans are four-to-five times as likely to develop open-angle glaucoma as are Caucasians. Similarly, open-angle glaucoma is much more prevalent in individuals over the age of 40, and especially in those over 60 years of age.
In addition, particular drugs have been associated with glaucoma. The corticosteroids (e.g., prednisone, dexamethasone, and hydrocortisone) are known to induce glaucoma following both ophthalmic and systemic administration systemic administration, by increasing resistance to aqueous humor outflow through the trabecular meshwork via a mechanism somehow genetically linked to primary open angle glaucoma. Dexamethasone has been associated with the most pronounced increase in intraocular pressure, and ophthalmic administration generally leads to greater increases than systemic administration.
Topically applied ophthalmic drugs which dilate the pupil (adrenergic agonists such as phenylephrine and epinephrine; anticholinergics such as atropine, scopolamine, homatropine, cyclopentolate and tropicarnide) may induce angle-closure glaucoma, while the anticholinergics can increase resistance to aqueous humor outflow in susceptible individuals even without causing angle-closure, apparently related to their cycloplegic (ciliary muscle/accommodation-paralyzing) action. Adrenergic (e.g., central nervous system stimulants, appetite suppressants) and anticholinergic (e.g., bowel relaxants and tricyclic antidepressants) agents administered systemically may also induce angle closure glaucoma, via secondarily dilating the pupil.
III. Therapeutic Modalities
Current glaucoma therapies are restricted to reducing intraocular pressure. Presently, both surgical and pharmacological treatments are used.
A. Surgical Treatment
Both laser and incisional surgical procedures are employed. Although open-angle glaucoma is generally controlled by pharmacological agents, laser trabeculoplasty or filtering surgery to improve aqueous drainage can be considered in severe cases. [See, e.g., The Merck Manual of Diagnosis and Therapy (16th Edition, 1992); Sec. 17: Ophthalmologic Disorders; Subsec. 227: Glaucoma; J. T. Wilensky and L. M. Jampol, "Laser therapy for open angle glaucoma," Ophthalmology 88:203-212 (1981)].
Because it constitutes a medical emergency, angle-closure glaucoma is the type of glaucoma that most frequently requires surgical intervention. As noted above, angle-closure glaucoma entails closure or blockage of the anterior chamber angle, thereby restricting outflow of aqueous humor. Angle-closure glaucoma can often be permanently cured by laser peripheral iridectomy performed within 12-48 hours after the onset of symptoms. [Current Surgical Diagnosis & Treatment (Eighth Edition, 1988), Appleton & Lange, Ch. 41, pp. 819-820]. Though often necessary and quite effective for both open- and closed-angle glaucoma, surgical intervention is an invasive form of treatment, even if local anesthesia can be used.
B. Pharmacological Treatment
Chronic open-angle glaucoma is generally treated by ocular administration of one of several agents. For a particular patient, the concentration of the agent and the frequency of administration is generally determined by trial and error, beginning with one of the weaker available preparations (e.g., pilocarpine 1%). The miotic agents (i.e., agents that causes the pupil to contract) represent one frequently used class of glaucoma drugs. Though the precise mechanism of action has not yet been fully elucidated, the miotic drugs lower intraocular pressure in patients suffering from open angle glaucoma by facilitating aqueous humor outflow, in turn consequent to mechanical deformation of the trabecular meshwork by drug-induced contraction of the ciliary muscle. The miotics, appropriately referred to as cyclotonics in this context, may be either direct-acting (e.g., pilocarpine and carbachol, which act on the muscarinic receptors of the ciliary muscle to produce contraction) or indirect-acting (e.g., anti-cholinesterases, such as echothiophate and isoflurophate, which prevent the degradation of the endogenous cholinergic neurotransmitter acetylcholine, thereby permitting strong and continuous contraction of the ciliary muscle). The adverse effects associated with the miotic agents include painful ciliary or accommodative spasm and consequent induced fluctuating myopia and blurred vision (in patients under the age of approximately 45 years), ciliary or conjunctival congestion, ocular pain, headache, and the miosis itself, which can cause a disabling reduction of vision in elderly patients with early cataract formation (the combination of the small pupil and the cloudy lens critically reduce the amount of light reaching the retina). The long-acting anticholinesterase are associated with the most severe and prolonged adverse effects, which may include development of cataracts or retinal detachment.
Several mydriatic agents are also useful in the initial treatment of open-angle glaucoma. For example, the sympathomimetic amines epinephrine and dipivefrin (a synthetic prodrug of epinephrine) lower intraocular pressure, at least in part through stimulation of .beta..sub.2 -adrenergic receptors in the trabecular meshwork (the mydriatic effect being irrelevant to the reduction in intraocular pressure). The adverse ocular effects of both agents include ocular congestion or hyperemia, ocular pain and headache, and blurred vision. In addition, epinephrine occasionally causes untoward systemic effects, such as palpitation, tachycardia, and hypertension.
In addition, the relatively new .alpha..sub.2 -adrenergic agonist apraclonidine has been shown to be effective in the treatment of glaucoma by inhibition of aqueous humor formation. As with many of the other topical anti-glaucoma preparations, apraclonidine is associated with both ocular (e.g., mydriasis and eyelid retraction) and systemic (e.g., dry mouth and nose) adverse effects.
Both non-selective .beta..sub.1 - and P.sub.2 -adrenergic blocking agents (e.g., timolol and levobunolol) and .beta..sub.1 -selective (e.g., betaxolol) adrenergic blocking agents are also used in the treatment of open-angle glaucoma. The mechanism of action likely entails reduction of aqueous humor formation. Adverse ocular effects include ocular stinging and discomfort, tearing, itching and/or foreign body sensation, and ocular dryness. Systemic cardiovascular and pulmonary adverse effects are of greater concern, are not uncommon especially in predisposed individuals (e.g., the elderly, patients with underlying cardiovascular or respiratory system disease, or those taking .beta.-adrenergic blocking agents systemically for other conditions), and may occasionally be life-threatening.
In general, the above-mentioned agents can be used in combination therapy. For example, pilocarpine can be added to a timolol regimen to achieve further reduction in intraocular pressure. Similarly, an orally administered carbonic anhydrase inhibitor (e.g., acetazolamide) can be added to an ocular regimen to enhance treatment. Many adverse effects have been associated with the oral carbonic anhydrase inhibitors, including gastrointestinal, central nervous system, hematologic, renal, electrolyte (especially dangerous in patients with heart disease taking digitalis and other salt-wasting diuretics concurrently), and metabolic disturbances. Of course, the potential incidence of adverse effects increases when more than one agent is being used in a treatment regimen. [See generally AHFS Drug Information 93, Gerald K. McEvoy, ed., pp. 1729-53 and 1767-79 (1993); The Merck Manual of Diagnosis and Therapy (16th Edition, 1992); Sec. 17: Ophthalmologic Disorders; Subsec. 227: Glaucoma].
As set forth above, untreated glaucoma can result in severe consequences, including blindness. Clearly, new treatment methods and agents are needed and would be welcomed by those plagued by glaucoma who either cannot tolerate available treatment regimens or who are unwilling to undergo invasive surgical procedures.